Recent studies from the laboratory have demonstrated that the massive hepatic necrosis in mice produced by the diuretic furosemide is mediated by the generation of reactive metabolites apparently derived from the 2-furyl methyl moeity of the molecule. Because of this finding and the close structural similarity of the thiophene residue contained in the nephrotoxic cephalosporins, cephaloridine andcephalothin, we have investigated the toxicology of furan and thiophene structural analogs. Simple 2-substituted furans and thiophenes induces a variety of tissue lesions in experimental animals including hepatic necrosis, renal tubular necrosis or combined hepatic and renal damage. Many, but not all, of these compounds also concomitantly deplete target organ glutathione. Alterations in target organ necrosis and glutathione depletion in pretreated animals implicate metabolic activations in the pathogenesis of those lesions. No correlation is apparent between target organ specificity, necrosis, or glutathione depletion and the chemical nature of the 2-substituent.